GHS-R1a deficiency mitigates lipopolysaccharide-induced lung injury in mice via the downregulation of macrophage activity.

Acute respiratory distress syndrome (ARDS) is a critical illness syndrome characterized by dysregulated pulmonary inflammation. Currently, effective pharmacological treatments for ARDS are unavailable. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHS-R1a), has a pivotal role in regulating energy metabolism and immunomodulation. The role of endogenous ghrelin in ARDS remains unresolved. Herein, we investigated the role of endogenous ghrelin signaling by using GHS-R1a-null (ghsr-/-) mice and lipopolysaccharide (LPS)-induced ARDS model. Ghsr-/- mice survived longer than controls after LPS-induced lung injury. Ghsr-/- mice showed lower levels of pro-inflammatory cytokines and higher oxygenation levels after lung injury. The peritoneal macrophages isolated from ghsr-/- mice exhibited lower levels of cytokines production and oxygen consumption rate after LPS stimulation. Our results indicated that endogenous ghrelin plays a pivotal role in initiation and continuation in acute inflammatory response in LPS-induced ARDS model by modulating macrophage activity, and highlighted endogenous GHS-R1a signaling in macrophage as a potential therapeutic target in this relentless disease.

NERP-2 regulates gastric acid secretion and gastric emptying via the orexin pathway.

Neuroendocrine regulatory peptide (NERP)-2 is derived from a distinct region of VGF, a neurosecretory protein originally identified as a product of a nerve growth factor-responsive gene in rat PC12 cells. Colocalization of NERP-2 with orexin-A in the lateral hypothalamus increases orexin-A-induced feeding and energy expenditure in both rats and mice. Orexigenic and anorectic peptides in the hypothalamus modulate gastric function. In this study, we investigated the effect of NERP-2 on gastric function in rats. Intracerebroventricular administration of NERP-2 to rats increased gastric acid secretion and gastric emptying, whereas peripheral administration did not affect gastric function. NERP-2-induced gastric acid secretion and gastric emptying were blocked by an orexin 1 receptor antagonist, SB334867. NERP-2 also induced Fos expression in the lateral hypothalamus and the dorsomotor nucleus of the vagus X, which are key sites in the central nervous system for regulation of gastric function. Atropine, a blocker of vagal efferent signal transduction, completely blocked NERP-2-induced gastric acid secretion. These results demonstrate that central administration of NERP-2 activates the orexin pathway, resulting in elevated gastric acid secretion and gastric emptying.

One-day high-fat diet induces inflammation in the nodose ganglion and hypothalamus of mice.

A high-fat diet (HFD) induces inflammation in systemic organs including the hypothalamus, resulting in obesity and diabetes. The vagus nerve connects the visceral organs and central nervous system, and the gastric-derived orexigenic peptide ghrelin transmits its starvation signals to the hypothalamus via the vagal afferent nerve. Here we investigated the inflammatory response in vagal afferent neurons and the hypothalamus in mice following one day of HFD feeding. This treatment increased the number of macrophages/microglia in the nodose ganglion and hypothalamus. Furthermore, one-day HFD induced expression of Toll-like receptor 4 in the goblet cells of the colon and upregulated mRNA expressions of the proinflammatory biomarkers Emr1, Iba1, Il6, and Tnfα in the nodose ganglion and hypothalamus. Both subcutaneous administration of ghrelin and celiac vagotomy reduced HFD-induced inflammation in these tissues. HFD intake triggered inflammatory responses in the gut, nodose ganglion, and subsequently in the hypothalamus within 24 h. These findings suggest that the vagal afferent nerve may transfer gut-derived inflammatory signals to the hypothalamus via the nodose ganglion, and that ghrelin may protect against HFD-induced inflammation.

Neuroendocrine regulatory peptide-2 stimulates glucose-induced insulin secretion in vivo and in vitro.

Neuroendocrine regulatory peptide (NERP)-2, recently identified as a bioactive peptide involved in vasopressin secretion and feeding regulation in the central nervous system, is abundantly expressed in endocrine cells in peripheral tissues. To explore the physiological roles of NERP-2 in the pancreas, we examined its effects on insulin secretion. NERP-2 increased glucose-stimulated insulin secretion (GSIS) in a dose-dependent manner, with a lowest effective dose of 10(-7) M, from the pancreatic ß-cell line MIN6 and isolated mouse pancreatic islets. NERP-2 did not affect insulin secretion under the low-glucose conditions. Neither NERP-1 nor NERP-2-Gly (nonamidated NERP-2) stimulated insulin secretion. NERP-2 significantly augmented GSIS after intravenous administration to anesthetized rats or intraperitoneal injection to conscious mice. We detected NERP-2 in pancreatic islets, where it co-localized extensively with insulin. Calcium-imaging analysis demonstrated that NERP-2 increased the calcium influx in MIN6 cells. These findings reveal that NERP-2 regulates GSIS by elevating intracellular calcium concentrations.

Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway from the hindbrain to the hypothalamus.

Ghrelin, a gastrointestinal peptide, stimulates feeding when administered peripherally. Blockade of the vagal afferent pathway abolishes ghrelin-induced feeding, indicating that the vagal afferent pathway may be a route conveying orexigenic ghrelin signals to the brain. Here, we demonstrate that peripheral ghrelin signaling, which travels to the nucleus tractus solitarius (NTS) at least in part via the vagus nerve, increases noradrenaline (NA) in the arcuate nucleus of the hypothalamus, thereby stimulating feeding at least partially through alpha-1 and beta-2 noradrenergic receptors. In addition, bilateral midbrain transections rostral to the NTS, or toxin-induced loss of neurons in the hindbrain that express dopamine beta hydroxylase (an NA synthetic enzyme), abolished ghrelin-induced feeding. These findings provide new evidence that the noradrenergic system is necessary in the central control of feeding behavior by peripherally administered ghrelin.

Therapeutic potential of ghrelin treatment for unloading-induced muscle atrophy in mice.

Ghrelin is a growth hormone (GH) secretagogue secreted mainly from the stomach that functions in controlling muscle volume and energy homeostasis. We here studied the effects of ghrelin on unloading-induced muscle atrophy using a mouse model of hindlimb suspension (HS). Ghrelin administration during 2-week HS alleviated reductions of muscle mass in the fast-twitch fiber-rich plantaris muscle and the slow-twitch fiber-rich soleus muscle of the hindlimb. Ghrelin administration during a 5-day recovery period following 2-week HS enhanced food intake and facilitated recovery from atrophy in both muscles. Ghrelin administration normalized hypercorticosteronemia in these studies. Ghrelin's anti-muscle atrophy effect was found even under pair-feeding condition, but not in mice given des-acyl ghrelin. Insulin-like growth factor (IGF)-1 mRNA expression was significantly reduced in the atrophied plantaris muscle compared with control muscles. A single ghrelin administration to HS mice acutely increased plasma GH and also amplified phosphorylation of signal transducer and activator of transcription (STAT) 5 and increased IGF-1 mRNA expression in the plantaris muscle, but not in the soleus muscle. This study demonstrated that ghrelin stimulated the GH-STAT5-IGF-1 axis in the locally atrophied plantaris muscle, and its administration alleviated muscle atrophy and facilitated recovery from muscle atrophy. Ghrelin's effects represent a novel therapeutic paradigm for the treatment of unloading-induced muscle atrophy induced by factors such as bed rest, injury, and joint immobilization.

Significant lowering of plasma ghrelin but not des-acyl ghrelin in response to acute exercise in men.

Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and growth hormone (GH) secretion via interaction with the GH secretagogue receptor. Ghrelin molecules are present in two major endogenous forms, an acylated form (ghrelin) and a des-acylated form (des-acyl ghrelin). Recent studies indicated that aerobic exercise did not change plasma total ghrelin levels, however, dynamics of circulating ghrelin and des-acyl ghrelin during aerobic exercise remains unclear. The purpose of this study is to examine the effects of moderate intensity exercise on plasma ghrelin and des-acyl ghrelin concentrations, and to investigate the relationship between ghrelin molecules and other hormonal and metabolic parameters during exercise. Nine healthy males (25.2 ± 0.5 years) exercised for 60 min at 50% of their maximal oxygen consumptions. We measured the plasma concentrations of ghrelin, des-acyl ghrelin, GH, norepinephrine (NE), epinephrine (E), dopamine (DA), insulin, and glucose. Plasma ghrelin level significantly decreased during exercise, whereas plasma des-acyl ghrelin and total ghrelin levels did not change. Plasma NE, E, DA and GH levels were significantly increased during exercise. Plasma insulin level significantly decreased during exercise, and plasma glucose levels remained steady during exercise. NE, E, DA, and GH were correlated negatively with plasma ghrelin levels. These findings suggest that acute moderate exercise may suppress ghrelin release from the stomach, decrease ghrelin O-acyltransferase activity, and/or activate ghrelin utilization in peripheral tissues and that exercise-induced ghrelin suppression may be mediated by activated adrenergic system.

Neuroendocrine regulatory peptide-2 regulates feeding behavior via the orexin system in the hypothalamus.

Neuroendocrine regulatory peptide (NERP)-1 and NERP-2 are derived from distinct regions of VGF, a neurosecretory protein. Vgf(-/-) mice exhibit dwarfism and hypermetabolic rates, suggesting that VGF or VGF-derived peptides play important roles in energy metabolism. Here, we examined the role of NERPs in the central regulation of feeding and energy homeostasis. We attempted to identify NERPs expressing neurons in rats by immunohistochemistry. We studied the effects of intracerebroventricular (icv) administration of NERP-2 on feeding, body temperature, oxygen consumption, and locomotor activity in rats and mice. Intracerebroventricular administration of NERP-2, but not NERP-1 or a form of NERP-2 bearing a COOH-terminal glycine extension, increased food intake in rats. We investigated the downstream signal of NERP-2 on the basis of studies of NERP-2-induced feeding with neutralization of orexins, neuropeptide Y, or agouti-related protein. NERP-2 expression localized to the lateral hypothalamus (LH) and the dorsomedial perifornical hypothalamus in rats, colocalizing with orexins that activate feeding behavior and arousal. NERP-2 administration induced Fos protein, a marker of neuronal activation, in the orexin-immunoreactive neurons. Vgf mRNA levels were upregulated in the rat LH upon food deprivation. Intracerebroventricular administration of NERP-2 also increased body temperature, oxygen consumption, and locomotor activity in rats. Treatment with anti-NERP-2 IgG decreased food intake. NERP-2-induced bioactivities could be abrogated by administration of anti-orexins IgG or orexin receptor antagonists. NERP-2 did not induce food intake or locomotor activity in orexin-deficient mice. Our findings indicate that hypothalamic NERP-2 plays a role in the control of food intake and energy homeostasis via the orexin pathway. Thus, VGF serves as a precursor of multiple bioactive peptides exerting a diverse set of neuroendocrine functions.

Functional interaction between Ghrelin and GLP-1 regulates feeding through the vagal afferent system.

The gastrointestinal tract transmits feeding-regulatory signals to the brain via neuronal and hormonal pathways. Here we studied the interaction between the orexigenic gastric peptide, ghrelin, and the anorectic intestinal peptide, glucagon-like peptide 1 (GLP-1), in terms of feeding regulation via the vagal afferents. GLP-1 preadministration 30 min before ghrelin administration to rats and mice abolished ghrelin-induced food intake, while ghrelin preadministration abolished the anorectic effect of GLP-1. Ghrelin preadministration suppressed GLP-1-induced Fos expression in the nodose ganglia (NG). Electrophysiological assessment confirmed that the initially administered peptide abolished the vagal afferent electrical alteration induced by the subsequently administered peptide. Both the growth hormone secretagogue receptor (GHSR) and the GLP-1 receptor (GLP-1R) are co-localised in a major proportion of NG neurons that innervate the stomach. In these Ghsr+Glp1r+ neurons, ghrelin preadministration abolished the GLP-1-induced calcium response. Ghrelin generated a hyperpolarising current and GLP-1 generated a depolarising current in isolated NG neurons in a patch-clamp experiment. Ghrelin and GLP-1 potently influenced each other in terms of vagally mediated feeding regulation. This peptidergic interaction allows for fine control of the electrophysiological properties of NG neurons.

Ontogeny of a new enteric peptide, neuropeptide W (NPW), in the developing rat stomach.

Neuropeptide W (NPW), a novel endogenous peptide for G protein-coupled receptors GPR7 and GPR8, is expressed in the gastric antral mucosa of rat, mouse, and human stomachs. Here, we studied the ontogeny of NPW in the developing rat stomach. Real-time RT-PCR showed that NPW gene expression was initially detectable in embryonic day 14 (E14) stomach and gradually increased during the progress of age until birth, postnatal day 1 (P1). NPW mRNA level in the stomach increased again from the weaning period (P21) until reaching adulthood. Immunohistochemistry using polyclonal antibodies raised against rat NPW revealed that NPW-positive cells were detected in the P1 antral stomach and gradually increased during the development of age. Furthermore, double immunohistochemistry demonstrated that NPW colocalized with gastrin in P1 rat stomach. These data will provide clues to physiological functions of NPW in the development of rat stomach.

The vagal afferent pathway does not play a major role in the induction of satiety by intestinal fatty acid in rats.

Intestinal infusion of long-chain fatty acids (LCFAs) strongly suppresses food intake and gut motility. Vagal afferents and cholecystokinin (CCK) signaling pathway are considered to play important roles in intestinal LCFA-induced satiety. Here, we first investigated the influence of vagus nerve on satiety following intestinal LCFA infusion in rats. Jejunal infusion of linoleic acid (LA) at 200 microL/h for 7 h suppressed food intake and the effect lasted for 24 h. The satiety induced by jejunal LA infusion occurred in a dose dependent manner. In contrast, the anorectic effect induced by octanoic acid, a medium-chain fatty acid, was weaker than that induced by LA. The reduction in food intake induced by jejunal LA infusion was not attenuated in rats treated with vagotomy, the ablation of bilateral subdiaphragmatic vagal trunks. Jejunal LA-induced satiety could also be observed in rats with bilateral midbrain transections, which ablates fibers between the hindbrain and hypothalamus. These findings suggest that the vagus nerve and fibers ascending from the hindbrain to the hypothalamus do not play a major role in intestinal LCFA-induced satiety. Jejunal LA infusion also reduced food intake in CCK-A receptor-deficient OLETF rats, suggesting that CCK signaling pathway is not critical for intestinal LCFA-induced anorexia. In conclusion, this study indicates that the vagus nerve and the CCK signaling pathway do not play major roles in conveying satiety signals induced by intestinal LCFA to the brain in rats.

Restoration of metabolic inflammation-related ghrelin resistance by weight loss.

High-fat diet (HFD)-induced metabolic inflammation in the central and peripheral organs contributes to the pathogenesis of obesity. Long-term HFD blunts signaling by ghrelin, a gastric-derived orexigenic peptide, in the vagal afferent nerve via a mechanism involving in situ activation of inflammation. This study was undertaken to investigate whether ghrelin resistance is associated with progressive development of metabolic inflammation. In mice, ghrelin's orexigenic activity was abolished 2-4 weeks after the commencement of HFD (60% of energy from fat), consistent with the timing of accumulation and activation of macrophages and microglia in the nodose ganglion and hypothalamus. Calorie-restricted weight loss after 12-week HFD feeding restored ghrelin responsiveness and alleviated the upregulation of macrophage/microglia activation markers and inflammatory cytokines. HSP72, a chaperone protein, was upregulated in the hypothalamus of HFD-fed mice, potentially contributing to prevention of irreversible neuron damage. These results demonstrate that ghrelin resistance is reversible following reversal of the HFD-induced inflammation and obesity phenotypes.

Analysis of peripheral ghrelin signaling via the vagus nerve in ghrelin receptor-restored GHSR-null mice.

The vagus nerve connects peripheral organs to the central nervous system (CNS), and gastrointestinal hormones transmit their signals to the CNS via the vagal afferent nerve. Ghrelin, a gastric-derived orexigenic peptide, stimulates food intake by transmitting starvation signals via the vagus nerve. To understand peripheral ghrelin signaling via the vagus nerve, we investigated the ghrelin receptor (GHSR)-null mouse. For this purpose, we tried to produce mice in which GHSR was selectively expressed in the hindbrain and vagus nerve. GHSR was expressed in some nodose ganglion neurons in these mice, but GHSR-expressing neurons were less abundant than in wild-type mice. Intraperitoneal administration of ghrelin did not induce food intake or growth hormone release, but did increase blood glucose levels. Our findings suggest that the abundance of GHSR-expressing neurons in the nodose ganglion is critical for peripheral administration of ghrelin-induced food intake and growth hormone release via the vagus nerve.

Ghrelin stimulates growth hormone secretion and food intake in aged rats.

Age-related decreases in energy expenditure have been associated with the loss of skeletal muscle and decline of food intake, possibly through a mechanism involving changes of growth hormone (GH) secretion and feeding behavior. Age-related declines of growth hormone secretion and food intake have been termed the somatopause and anorexia of ageing, respectively. Ghrelin, a 28-amino-acid peptide, was isolated from human and rat stomachs as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin stimulates growth hormone release and food intake when peripherally administered to rodents and humans. Here, we investigate the relationship between age-related decline of growth hormone secretion and/or food intake and ghrelin function. Ghrelin (10 nmol/kg body weight) was administered intravenously to male 3-, 12-, 24-and 27-month-old Long-Evans rats, after which growth hormone concentrations and 2 h food intake were measured. An intravenous administration of ghrelin to rats increased food intake in all generations. In addition, to orexigenic effect by ghrelin, intravenous administration of ghrelin elicited a marked increase in plasma GH levels, with the peak occurring 15 min after administration. These findings suggest that the aged rats maintain the reactivity to administered exogenous ghrelin.

[Hormone replacement Up-to-date. Ghrelin, growth hormone and somatopause].

Age-related decreases in energy expenditure and physical activity have been associated with the loss of skeletal muscle and decline of food intake, possibly through a mechanism involving changes of growth hormone secretion and feeding behavior. Age-related declines of growth hormone secretion and food intake have been termed the somatopause and anorexia of aging, respectively. Ghrelin was isolated from human and rat stomachs as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin stimulates growth hormone release and food intake when peripherally administered to humans. Plasma ghrelin concentration is decreased with age. Therefore, age-related decline of ghrelin secretion may cause the somatopause and anorexia of aging. Ghrelin replacement may suppress these aging processes.

Maternal ghrelin plays an important role in rat fetal development during pregnancy.

Ghrelin, an acylated peptide serving as an endogenous ligand for GH secretagogue receptor (GHS-R), was originally isolated from rat and human stomach. In this study, we report the critical role of maternal ghrelin in fetal development. High levels of ghrelin receptor (GHS-R) mRNA were detected in various peripheral fetal tissues beginning at embryonic d 14 and lasting until birth. Fetal GHS-R expression was also confirmed in fetal tissues by immunohistochemistry. Autoradiography revealed that both des-acyl ghrelin and acyl ghrelin bind to fetal tissues. Chronic treatment of mothers with ghrelin resulted in a significant increase in birth weight in comparison to newborns from saline-treated mothers. Even when maternal food intake after ghrelin treatment was restricted through paired feeding, significant stimulation of fetal development still occurred. Conversely, active immunization of mothers against ghrelin decreased fetal body weight during pregnancy. A single ghrelin injection into the mother increased circulating ghrelin levels in the fetus within 5 min of injection, suggesting that maternal ghrelin transits easily to the fetal circulation. High levels of des-acyl ghrelin were detected in fetal blood and amniotic fluid. Both acylated and des-acyl ghrelin increased [3H]thymidine and 5-bromo-2'-deoxyuridine incorporation of cultured fetal skin cells in a dose-dependent manner, and calcium-imaging analysis revealed that acyl and des-acyl ghrelin increased the Ca2+ influx in discrete cultured fetal skin cells, respectively. These results indicate that maternal ghrelin regulates fetal development during the late stages of pregnancy.

Central effects of calcitonin receptor-stimulating peptide-1 on energy homeostasis in rats.

The CT-R [calcitonin (CT) receptor] is expressed in the central nervous system and is involved in the regulation of food intake, thermogenesis, and behaviors. CT-R-stimulating peptide-1 (CRSP-1), a potent ligand for the CT-R, was recently isolated from the porcine brain. In this study, we first confirmed that porcine CRSP-1 (pCRSP-1) enhanced the cAMP production in COS-7 cells expressing recombinant rat CT-R, and then we examined the central effects of pCRSP-1 on feeding and energy homeostasis in rats. Intracerebroventricular (icv) administration of pCRSP-1 to free-feeding rats suppressed food intake in a dose-dependent manner. Chronic icv infusion of pCRSP-1 suppressed body weight gain over the infusion period. Furthermore, icv administration of pCRSP-1 increased body temperature and decreased locomotor activity. The central effects of pCRSP-1 were more potent than those of porcine CT in rats. In contrast, ip administration of pCRSP-1 did not elicit any anorectic or catabolic effects. Administration icv of pCRSP-1 also induced mild dyskinesia of the lower extremities and decreased gastric acid output. Fos expression induced by icv administration of pCRSP-1 was detected in the neurons of the paraventricular nucleus, dorsomedial hypothalamic nucleus, arcuate nucleus, locus coeruleus, and nucleus of solitary tract, areas that are known to regulate feeding and energy homeostasis. Administration icv of pCRSP-1 increased plasma concentrations of ACTH and corticosterone, implying that the hypothalamic-pituitary-adrenocortical axis might be involved in catabolic effects of pCRSP-1. These results suggest that CRSP-1 can function as a ligand for the CT-R and may act as a catabolic signaling molecule in the central nervous system.

Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor.

Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and GH secretion via interactions with the GH secretagogue type 1a receptor (GHS-R1a), the functionally active form of the GHS-R. Ghrelin molecules exist in the stomach and hypothalamus as two major endogenous forms, a form acylated at serine 3 (ghrelin) and a des-acylated form (des-acyl ghrelin). Acylation is indispensable for the binding of ghrelin to the GHS-R1a. Ghrelin enhances feeding via the neuronal pathways of neuropeptide Y and orexin, which act as orexigenic peptides in the hypothalamus. We here studied the effect of des-acyl ghrelin on feeding behavior. Intracerebroventricular (icv) administration of rat des-acyl ghrelin to rats or mice fed ad libitum stimulated feeding during the light phase; neither ip nor icv administration of des-acyl ghrelin to fasting mice suppressed feeding. The icv administration of des-acyl ghrelin induced the expression of Fos, a marker of neuronal activation, in orexin-expressing neurons of the lateral hypothalamic area, but not neuropeptide Y-expressing neurons of the arcuate nucleus. Peripheral administration of des-acyl ghrelin to rats or mice did not affect feeding. Although icv administration of ghrelin did not induce food intake in GHS-R-deficient mice, it did in orexin-deficient mice. In contrast, icv administration of des-acyl ghrelin stimulated feeding in GHS-R-deficient mice, but not orexin-deficient mice. Des-acyl ghrelin increased the intracellular calcium concentrations in isolated orexin neurons. Central des-acyl ghrelin may activate orexin-expressing neurons, perhaps functioning in feeding regulation through interactions with a target protein distinct from the GHS-R.

Central Insulin Action Activates Kupffer Cells by Suppressing Hepatic Vagal Activation via the Nicotinic Alpha 7 Acetylcholine Receptor.

Central insulin action activates hepatic IL-6/STAT3 signaling, which suppresses the gene expression of hepatic gluconeogenic enzymes. The vagus nerve plays an important role in this centrally mediated hepatic response; however, the precise mechanism underlying this brain-liver interaction is unclear. Here, we present our findings that the vagus nerve suppresses hepatic IL-6/STAT3 signaling via α7-nicotinic acetylcholine receptors (α7-nAchR) on Kupffer cells, and that central insulin action activates hepatic IL-6/STAT3 signaling by suppressing vagal activity. Indeed, central insulin-mediated hepatic IL-6/STAT3 activation and gluconeogenic gene suppression were impeded in mice with hepatic vagotomy, pharmacological cholinergic blockade, or α7-nAchR deficiency. In high-fat diet-induced obese and insulin-resistant mice, control of the vagus nerve by central insulin action was disturbed, inducing a persistent increase of inflammatory cytokines. These findings suggest that dysregulation of the α7-nAchR-mediated control of Kupffer cells by central insulin action may affect the pathogenesis of chronic hepatic inflammation in obesity.

The role of the vagal nerve in peripheral PYY3-36-induced feeding reduction in rats.

Peptide YY (PYY), an anorectic peptide, is secreted postprandially from the distal gastrointestinal tract. PYY(3-36), the major form of circulating PYY, binds to the hypothalamic neuropeptide Y Y2 receptor (Y2-R) with a high-affinity, reducing food intake in rodents and humans. Additional gastrointestinal hormones involved in feeding, including cholecystokinin, glucagon-like peptide 1, and ghrelin, transmit satiety or hunger signals to the brain via the vagal afferent nerve and/or the blood stream. Here we determined the role of the afferent vagus nerve in PYY function. Abdominal vagotomy abolished the anorectic effect of PYY(3-36) in rats. Peripheral administration of PYY(3-36) induced Fos expression in the arcuate nucleus of sham-operated rats but not vagotomized rats. We showed that Y2-R is synthesized in the rat nodose ganglion and transported to the vagal afferent terminals. PYY(3-36) stimulated firing of the gastric vagal afferent nerve when administered iv. Considering that Y2-R is present in the vagal afferent fibers, PYY(3-36) could directly alter the firing rate of the vagal afferent nerve via Y2-R. We also investigated the effect of ascending fibers from the nucleus of the solitary tract on the transmission of PYY(3-36)-mediated satiety signals. In rats, bilateral midbrain transections rostral to the nucleus of the solitary tract also abolished PYY(3-36)-induced reductions in feeding. This study indicates that peripheral PYY(3-36) may transmit satiety signals to the brain in part via the vagal afferent pathway.